Location of the MT-CO2 gene in the human mitochondrial genome. MT-CO2 is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes).
Cytochrome c oxidase subunit II, transmembrane domain
The MT-CO2 gene encodes for the second subunit of cytochrome c oxidase (complex IV), a component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water. MT-CO2 is one of the three subunits which are responsible for the formation of the functional core of the cytochrome c oxidase. MT-CO2 plays an essential role in the transfer of electrons from cytochrome c to the bimetallic center of the catalytic subunit 1 by utilizing its binuclear copper A center. It contains two adjacent transmembrane regions in its N-terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. MT-CO2 provides the substrate-binding site and contains the binuclear copper A center, probably the primary acceptor in cytochrome c oxidase.[12][13][5]
Clinical significance
Mitochondrial complex IV deficiency
Variants of MT-CO2 have been associated with the mitochondrialComplex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain that catalyzes the oxidation of cytochrome c utilizing molecular oxygen.[14] The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental disability, delayed motor development and mental retardation.[15] Mutations of MT-CO2 is also known to cause Leigh's disease, which may be caused by an abnormality or deficiency of cytochrome oxidase.[9][8]
A wide range of symptoms have been found in patients with pathogenic mutations in the MT-CO2 gene with the mitochondrialComplex IV deficiency. A deletion mutation of a single nucleotide (7630delT) in the gene has been found to cause symptoms of reversible aphasia, right hemiparesis, hemianopsia, exercise intolerance, progressive mental impairment, and short stature.[16] Furthermore, a patient with a nonsense mutation (7896G>A) of the gene resulted in phenotypes such as short stature, low weight, microcephaly, skin abnormalities, severe hypotonia, and normal reflexes.[17] A novel heteroplasmic mutation (7587T>C) which altered the initiation codon of the MT-CO2 gene in patients have shown clinical manifestations such as progressive gait ataxia, cognitive impairment, bilateral optic atrophy, pigmentary retinopathy, a decrease in color vision, and mild distal-muscle wasting.[18]
Others
Juvenile myopathy, encephalopathy, lactic acidosis, and stroke have also been associated with mutations in the MT-CO2 gene.[5]
Interactions
MT-CO2 is known to interact with cytochrome c by the utilization of a lysine ring around the carboxyl containing heme edge of cytochrome c in MT-CO2, including glutamate 129, aspartate 132, and glutamate 19.
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